The social and healthcare costs attendant on the aging of human populations throughout the developed world make research into potential therapies to enhance healthy life span particularly timely. Traditional research on mechanisms of senescence-retardation employs animal species that in contrast to humans exhibit poor defenses against the destructive process of aging. An alternative approach embodied in this proposal is to interrogate species with exceptional resistance to aging processes about the mechanisms by which they do so in the hope and expectation that understanding such mechanisms might lead to effective senescence-retarding therapies for long-lived species such as humans. The proposed research involves a unique collaboration between marine biologists at Bangor University in the UK and biogerontologists at the University of Texas Health Science Center San Antonio in the US to investigate mechanisms of aging in bivalve molluscs, including the ocean quahog (Arctica islandica) which is the longest-lived animal known with longevity documented at over 400 years. Many species of biivalve molluscs can be aged precisely from their shell morphology, can be collected in large numbers and transported alive to research laboratories and exhibit a range of longevities in natural populations ranging from about 1 year maximum to more than 400 years. These traits in sum make them a potentially vastly informative group to study in a comparative perspective to discover mechanisms modulating aging rate. Our overall hypothesis is that one or more mechanisms of aging suggested by investigations of traditional species will contribute to the unheard of range of longevities observed in bivalve molluscs. In the service of this hypothesis we will use 7 bivalve species encompassing the full range of longevities noted above to perform three specific aims: (1) evaluate the hypothesis that mitochondrial efficiency in producing ATP while minimizing reactive oxygen species production is a critical determinant of species longevity;in order to assess this hypothesis we will carry out a comprehensive analysis of mitochondrial function in all species;(2) evaluate the hypothesis that proteome stability is a critical longevity determinant, using a range of assays of protein quality, stability, and rate of turnover;and (3) evaluate the hypothesis that the ability to resist stress is a critical determinant of longevity by exposing our 7 species to a potent oxidative stressor and assaying tissue level damage by proteins, lipids, and DNA done by the stressor as well as the rate of repair/recovery. By the end of this 3 year project, we should have developed sufficient informative data and reciprocal expertise between the participating laboratories to develop this novel research system further in subsequent grant applications. PUBLIC HEALTH RELEVANCE: This proposal seeks to determine mechanisms that retard aging with the long-term goal of the development of therapies to slow human aging, thereby enhancing and preserving human health. Because aging is the ultimate cause of many late life maladies, the research has the potential to not only enhance health but delay and mitigate numerous late life diseases.